Investigational New Drugs最新文献

Pembrolizumab has shown links to autoimmune encephalitis (AE), yet the exact clinical characteristics remain unclear. This study examines the clinical features of pembrolizumab-induced AE to enhance diagnostic accuracy and therapeutic strategies. Reports on pembrolizumab-induced AE were gathered via a searchable database, culminating on November 30, 2024. The median age at onset among the 34 patients was 68 years (range 47-82), with males constituting 67.6%. The average onset period for AE was 6 months (range 0.3-25) after the initial dose, with an average of 6 cycles (range 1-17). Commonly reported symptoms included confusion (38.2%), fever (35.3%), and decreased consciousness (32.4%). Cerebrospinal fluid analysis revealed elevated protein (55.9%), leukocytosis (70.6%), and normal blood glucose levels (38.2%). Antineuronal antibodies were found to be negative in 41.2% of cases and positive in 35.3%. Magnetic resonance imaging indicated T2/FLAIR hypersignal in 32.4% of cases, while the electroencephalogram revealed slow waves (11.8%) and diffuse slowing (11.8%). Following treatment with steroids, intravenous immunoglobulin, and plasmapheresis, 82.4% of patients experienced symptom improvement or recovery, though 5.9% succumbed to AE. Oncologists must consider the risk of AE when prescribing pembrolizumab. Early diagnosis and intervention for AE are crucial. Further research is needed to define the optimal treatment approach.

Multiple myeloma (MM) is a prevalent bone marrow cancer that often presents challenges due to treatment resistance. This study assessed the apoptotic and antiproliferative effects of the Polo-like kinase 1 inhibitor MLN0905, alone and in combination with lenalidomide, in an MM cell line. The AMO1 human MM cell line was treated with various doses of lenalidomide, MLN0905, or their combination. Cell viability was assessed via the MTT assay, and apoptosis was quantified via Annexin V/propidium iodide staining. The effects of treatment on BCL2, p21, and PUMA gene expression were evaluated through quantitative real-time polymerase chain reaction. The IC50 values were 50.61 μM for lenalidomide and 54.27 nM for MLN0905, indicating dose-dependent cytotoxic effects. When 30 μM lenalidomide was combined with 50 nM MLN0905, the percentage of apoptotic cells increased to 51.31%. The SynergyFinder platform identified optimal synergy at 40 μM lenalidomide plus 50 nM MLN0905. MLN0905 significantly reduced p21, PUMA, and BCL2 mRNA levels, whereas lenalidomide increased p21 and PUMA mRNA expression and decreased BCL2 expression. The combination treatment notably increased p21 expression and significantly reduced BCL2 levels, with no marked change in PUMA mRNA. This study revealed that MLN0905 significantly affects AMO1 cell survival, reducing the mRNA expression of genes involved in apoptosis and the cell cycle in a dose-dependent manner. Furthermore, the combination of lenalidomide and MLN0905 synergistically decreases cell survival and induces apoptosis in AMO1 cells. The altered expression of apoptotic genes highlights the potential of this drug combination for future multiple myeloma research.

Background: Immune checkpoint inhibitors (ICIs) combined with anti-vascular endothelial growth factor (VEGF) have been the standard first-line treatment of hepatocellular carcinoma (HCC). However, the efficacy of this combination in post-line treatment is still unknown. This study aimed to evaluate the efficacy and safety of the combination of anti-PD-L1 envafolimab and novel humanized anti-VEGF suvemcitug as second-line treatment for patients with HCC.

Methods: This open-label, prospective phase II clinical study (NCT05148195) comprised safety run-in stage and dose expansion stage of HCC cohort. Eligible patients were aged ≥ 18 years and had undergone at least a prior line of treatment. Patients received fixed-dose envafolimab and suvemcitug until termination of disease progression, unacceptable toxicities, or withdrawal. The primary endpoint of safety run-in stage was recommended dose (RD), and dose expansion stage was objective response rate (ORR).

Results: As of August 10, 2023, no dose-limiting toxicity was observed in six patients in the safety-run-in stage, and 2 mg/kg dose every 3 weeks was declared the RD of suvemcitug. Among 20 patients with HCC, the median age was 54.5 (range, 42-70) years. Of these patients, 20 (100.0%) received ≥ one prior line treatment, with 20 (100%) received tyrosine kinase inhibitor (TKI) treatment and 8 (40.0%) received prior ICI treatment. The ORR was 10.0% (95% confidence interval (CI), 1.2-31.7), DCR was 65.0% (95% CI, 40.8-84.6), and DoR was not reached (NR). With a median follow-up of 13.9 months, the median progression-free survival (PFS) and median overall survival (OS) were 4.3 months (95% CI, 1.4-8.1) and 10.7 months (95% CI, 6.0-not evaluable [NE]), respectively. Treatment-related adverse events (TRAEs) of grade ≥ 3 occurred in 40% patients, with proteinuria (20.0%, 4/20) being the most frequent. The ORR of no lung metastasis, prior first-line treatment and IO naïve treatment subgroup was 16.7%.

Conclusions: The combination of envafolimab and suvemcitug showed a tolerable safety profile and promising antitumor activity in HCC patients who failed later-line treatment.

Acute myeloid leukemia (AML) is a malignant clonal hematological tumor originating from immature myeloid cells and is the most prevalent type of leukemia in adults. Traditional chemotherapy regimens based on cytarabine and anthracycline agents are associated with a high relapse rate. Therefore, investigation of novel targeted therapies is crucial for improving AML treatment outcomes. In this study, we found that CTI-2, a novel inhibitor of perinucleolar compartment (PNC), has potential anti-AML activity with a favorable safety profile. CTI-2 induced a greater degree of apoptosis in FLT3-ITD mutant AML cells compared to AML cells with wild-type FLT3 mainly through the intrinsic apoptotic pathway. Furthermore, MK2 and Pim-1 were identified as potential targets of CTI-2 through molecular docking analysis. CTI-2 decreased both the overall expression level and the phosphorylation of c-Myc, which are regulated by MK2 and Pim-1, respectively. Notably, CTI-2 exhibited a more substantial inhibitory effect on c-Myc in FLT3-ITD mutant cells, which may contribute to the enhanced efficacy of CTI-2 in this specific subset of AML. In summary, we have conducted a preliminary investigation into the anti-AML activity and underlying mechanisms of CTI-2. These results provide clues for the targeting of PNC in the treatment of AML.

SL-279252 is a bifunctional hexameric fusion protein adjoining the extracellular domains of PD-1 and OX40L via an inert IgG4 derived Fc domain. A Phase 1 dose escalation study was conducted in patients (pts) with advanced solid tumors or lymphomas. SL-279252 was administered intravenously across 12 dose levels (range: 0.0001-24 mg/kg). Objectives included evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, pharmacokinetic and pharmacodynamic (PD) parameters, and anti-tumor activity. Forty-nine pts (48 with solid tumor and 1 with lymphoma) were enrolled (median age 64 years; 53% male; median [range] of 3 [0-5] prior systemic therapies; 61% had been previously treated with PD-1/L1 inhibitors). Most common treatment-related adverse events (AEs) were infusion-related reaction (16%), maculopapular rash (10%), fatigue (6%), and neutropenia (6%). Treatment-related Grade (G) 3 AE was neutropenia (4%). There were no G4 or G5 AEs or DLTs. SL-279252 Cmax and area under the curve (AUC) increased proportionally with dose. T½ was ~ 20 h. Baseline anti-drug antibodies (ADA) were observed in 11/42 pts who had received a PD-1 inhibitor within 250 days. 7/31 pts had a persistent SL-279252 induced ADA response. PD effects consistent with OX40 engagement included dose dependent egress of CD4 + OX40 + cells and increases in Ki67 + CD4 and CD8 central and effector memory cells in the blood. Best response by iRECIST [1] in 46 response evaluable subjects was 1 iPR and 15 iSD. SL-279252 was well tolerated. PD effects consistent with OX40 activation were observed, however, efficacy was limited which may have been due to the disease characteristics, prior treatment with PD-1/L1 inhibitors, neutralization of the PD-1 domain of SL-279252 by circulating PD-1 inhibitors, limited SL-279252 penetration into tumors or other variables. Trial register number NCT03894618. Trial registration date 28-March-2019.

HER2 and EGFR are frequently co-expressed in various tumors. While antibody-drug conjugates (ADCs) targeting HER2, such as T-DM1 and T-Dxd, have shown remarkable antitumor effects in clinical responses, their effectiveness is constrained by drug resistance. EGFR amplification or high expression is one of the factors that lead to resistance against HER2-targeted ADCs. Likewise, the amplification of HER2 may lead to the development of resistance to EGFR-targeted therapies. To overcome these challenges, we, therefore, developed a bispecific antibody (B2C4) that targets HER2 and EGFR. B2C4 exhibited strong binding affinity and internalization activity in tumor cells with high expression of HER2 and EGFR, as well as in those with high expression of either target. B2C4 was then conjugated with vc-MMAE to create a bispecific ADC (B2C4-MMAE) with an average DAR of 4.05. By effectively engaging both arms of the bispecific ADC, B2C4-MMAE demonstrated significant antitumor activity in tumor cells and animal models that were unresponsive HER2- or EGFR-targeted ADCs. B2C4-MMAE could serve as an alternative therapeutic option for tumors that are resistant to single-target treatments. Additionally, B2C4-MMAE exhibited potential in treating tumors resistant to T-Dxd, underscoring its promise as a treatment for challenging cases.

To study the clinical features of nivolumab-induced immune-related pancreatitis and to provide evidence for its recognition and treatment. Cases of nivolumab-induced pancreatitis were collected by searching Chinese and English databases until November 30, 2024. Forty-three patients were included, with a median age of 61 years (range 23, 79). The median time to onset of pancreatitis was 120 days (range 1, 990) after initial administration. The main symptoms of the patients were abdominal pain (55.8%), nausea (14.0%), vomiting (11.6%), fever (9.3%), anorexia (9.3%), and asymptomatic (7.0%). Laboratory tests showed elevated lipase and amylase levels, with median values of 391.5 IU/L (range 136, 4050) and 1588 IU/L (range 248, 8788), respectively. Pancreatic biopsy showed inflammatory cell infiltration (18.6%), fibrosis (7.0%), and acinar damage and dropout (4.7%). The main imaging findings were focal or diffuse enlargement of the pancreas and fat stranding. After discontinuation of nivolumab and receiving steroid and immunosuppressive therapy (88.4%), patients' symptoms improved at a median time of 42 days (range 7, 192), and 11.6% of patients died. Immune-related pancreatitis should be alert during nivolumab administration. The lack of specificity of clinical symptoms and laboratory tests confuses the diagnosis of pancreatitis. The diagnosis of immune-associated pancreatitis should be treated promptly.

Poly(ADP-ribose) polymerase (PARP) inhibitors may have cardioprotective properties. This study aimed to evaluate the potential cardioprotective effects of PARP inhibitors in patients with epithelial ovarian cancer treated with platinum-based chemotherapeutic agents. A retrospective cohort study was conducted using the Health Insurance Review & Assessment Service claims database from January 2007 to July 2022. Eligible patients were those diagnosed with ovarian, primary peritoneal, or fallopian tube cancer who received platinum-based chemotherapy after 2017. Propensity score matching was employed to adjust for potential confounders, and logistic regression and Cox proportional hazards regression analyses were utilized to estimate the odds ratios, hazard ratios, and 95% confidence intervals (CIs) for the occurrence of cardiac adverse events, including myocardial infarction, cardiomyopathy, and heart failure. A total of 7,253 eligible patients were included in the study, of which 233 (3.2%) used PARP inhibitors. After propensity score matching, no significant cardioprotective effect was observed in the PARP inhibitor-exposed group compared to the non-exposed group (adjusted odds ratio, 0.753; 95% CI 0.275-2.059; adjusted hazard ratio, 0.601; 95% CI 0.228-1.584). Although no statistically significant cardioprotective effect of PARP inhibitors was found in this study, there was a directional trend suggesting that patients with gynecologic malignancies treated with platinum-based chemotherapy could potentially benefit from PARP inhibitors. Further research with larger sample sizes and longer follow-up periods is warranted to elucidate the role of PARP inhibitors in mitigating cardiac adverse events in this patient population.